Characterization of intestinal regeneration in a model of intestinal atresia

描述(由申请人提供)：在这项建议中，我们使用先天人类缺陷的遗传小鼠模型来研究以前未知的胚胎肠道内的再生机制。先天性缺陷是一种在产前形成的肠道闭锁，导致部分肠管的节段性缺失。Atresias在新生儿期表现为肠梗阻。相当大比例的肠闭锁患者会出现短肠综合征/肠衰竭(SGS/IF)，即肠道缺乏足够的长度和表面积来吸收足够的卡路里，以满足营养需求。目前，SGS/IF的治疗选择有限，适用于这些患者的一部分。这项拟议的研究将探索胚胎肠道的再生潜力。这一点意义重大，因为没有任何治疗方法能够使我们实现在SGS/IF中利用患者自己的细胞来取代肠道的长期目标。这项研究具有创新性，因为它开启了两种范式转变的可能性。第一种可能性是我们的实验室认识到胚胎肠道在损伤后具有再生的潜力。第二种可能性是，再生需要从 一个胚层(中胚层)转分化并作为一种细胞类型发挥功能，通常来自单独的胚层(内胚层)：这一过程也被称为谱系重新编程。目的1将验证这一假设，即在闭锁形成的后凋亡阶段，内胚层小室受到侧板中胚层来源的细胞谱系的侵袭。目标2将测试入侵细胞是否能够完全转分化，并在入侵后承担内皮命运。这些假设是根据我的实验室的初步数据提出的。预期的结果将阐明一种新的再生机制，使肠道能够重建内胚层隔室，并挽救损伤后的发育。预期的结果将在以前未知的肠道发育领域开辟一条全新的调查路线。此外，它们将是利用这一反应实现我们为SGS/IF患者开发再生疗法的非常长期目标的下一步：SGS/IF是一种在这个国家折磨着20,000多名患者(NIH-PA-06-230)的疾病。

DESCRIPTION (provided by applicant): In this proposal we use a genetic mouse model of a congenital human defect to study a previously unknown regenerative mechanism within the embryonic intestine. The congenital defect is an intestinal atresia which forms prenatally and results in a segmental absence of a portion of the intestinal tube. Atresias present in the newborn period as an intestinal obstruction. A significant percentage of patients with intestinal atresia develop shortgut syndrome/Intestinal failure (SGS/IF), a condition where the intestine lacks sufficient length and surface area to absorb adequate calories in order to meet nutritional requirements. Currently, the therapeutic options for SGS/IF are limited and applicable to a subset of these patients. The proposed research will explore the regenerative potential of the embryonic intestine. This is significant because there are no therapies that enable us achieve our long-range goal of utilizing the patient's own cells to replace intestine in SGS/IF. This research is innovative because it has opened up the possibility of two paradigm shifts. The first possibility is the recognition by our laboratory that the embryonic intestine has the potential to regenerate after injury. The second possibility is that regeneration requires a cell derived from a one germ layer (mesoderm) to transdifferentiate and function as a cell type normally derived from a separate germ layer (endoderm): a process also known as lineage reprogramming. Aim 1 will test the hypothesis that the endoderm compartment is invaded by a lateral plate mesoderm derived lineage of cells during the post-apoptotic phase of atresia formation. Aim 2 will test whether the invading cells are capable of fully transdifferentiating and assuming an endodermal fate following invasion. These hypotheses were formulated out of preliminary data from my laboratory. The expected results will illuminate a novel regenerative mechanism that enables the intestine to reconstitute the endoderm compartment and rescue development after injury. Expected results will open up an entirely new line of investigation in a previously unknown area of intestinal development. Furthermore, they will be the next steps towards exploiting this response to realize our very long-term goal of developing regenerative therapies for patients with SGS/IF: a disease that afflicts over 20,000 patients (NIH- PA-06-230) in this country.